Biological treatment in rheumatoid arthritis: when to stop?

October 26, 2013. http://dx.doi.org/10.1016/. S0140-6736(13)61941-8.  

Randomised controlled trials of the eff ect of stopping treatment are rare, but in The Lancet Josef Smolen and colleagues1 report results showing that it is possible to stop a risky and expensive treatment for many patients with rheumatoid arthritis once an initial response has been obtained. Newly diagnosed adult patients were treated fi rst with either methotrexate plus placebo (n=517) or methotrexate plus the biological drug adalimumab (n=515), a fully human monoclonal antibody that binds to tumour necrosis factor (TNF), preventing it from activating TNF receptors.

More patients in the methotrexate plus adalimumab group (207 of 466 [44%] completers, 40% of patients randomised) attained a predefi ned low disease activity target (28-joint disease activity score with C-reactive protein [DAS28] <3·2) at weeks 22 and 26 compared with methotrexate alone (112 of 460 [24%] completers, 22% of patients randomised).1,2

Patients with low disease activity in the methotrexate plus adalimumab group were then randomly allocated to continue this treatment, or to switch to methotrexate plus placebo. Patients who achieved the target with methotrexate monotherapy continued that regimen. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexatemonotherapy, and was achieved by more patients in the adalimumab-continuation group (73 of 105 [70%]) than the methotrexate-monotherapy group (61 of 112 [54%]; mean diff erence 15% [95% CI 2–28]). However, importantly, outcomes for clinical symptoms and radio graphic progression were assessed in all groups at week 78—by which time patients who withdrew adalimumab mostly maintained their good responses.

This study—the OPTIMA trial—was very large (more than 1000 patients at 161 sites), and in our opinion excellently done, properly analysed, and appropriately interpreted. And yet we fi nd ourselves interpreting the result in a wider context than the investigators, who comment that withdrawal of the biological agent might be an option for most patients with early rheumatoid arthritis who achieve initial disease control. We think this study raises three other questions: did the patients need to take biological therapy in the fi rst place? Was there another treatment eff ect hidden within the trial results? And how should the cost-eff ectiveness of biological therapy be calculated?

The initial control group of this study was methotrexate plus placebo, but scientifi c literature on the treatment of newly diagnosed rheumatoid arthritis, some reported since OPTIMA was designed, very strongly suggests that methotrexate monotherapy is an inadequate and old fashioned therapy. Combination therapy, particularly including glucocorticoids (which we advocate in our practice) would be a more appropriate comparator group,3–6 and some would argue that a so-called treat-to-target policy of dose escalation would be even more eff ective (although its cost-eff ectiveness has not yet been shown).6,7 Indeed, these combination therapies have been shown to produce treatment eff ects very similar to biological therapies. We would no longer off er monotherapy with methotrexate to our patients except in rare circumstances. Trial comparisons should compare new treatments to the best available alternative, but many do not. Showing that a new treatment is better than an old treatment that has been superseded does not add useful knowledge.

Other treatments were used in OPTIMA; in particular, more than 40% of patients were treated with glucocorticoids during the fi rst 26 weeks of the study. As is common in most trial reports, the random allocation of patients meant that roughly equal proportions of patients were taking glucocorticoids in each group, and hence the trial interpretation often ignores this aspect of treatment. But the evidence shows an additional eff ect of glucocorticoids added to other disease modifying therapies,3–6 such as methotrexate. Might it be that the therapeutic benefi ts are also heightened in those patients taking glucocorticoids at the same time as biological therapies? The data from this and other studies of biological therapies should be analysed from this point of view.

How do we estimate the cost-eff ectiveness of

expensive treatments such as biological therapy?

Their cost is an order of magnitude greater than

those of combinations of standard treatment plus

glucocorticoids. In most countries, biological therapy

is only reimbursed when methotrexate and one other

traditional antirheumatic drug have failed. In the UK,

the National Institute for Health and Care Excellence

(NICE) has applied the clinical trial outcomes from

biological therapy to a mathematical model of costs

and benefi ts, resulting in a strict reimbursement rule

compared with many other European countries.8

And even in NICE’s analysis cost-eff ectiveness of

biological agents might be exaggerated, because the

model compares biological agents with methotrexate

monotherapy rather than the more eff ective

combination therapy. In this situation, were healthcare

providers to change the practice for initial

treatment of rheumatoid arthritis on the basis of

OPTIMA, all patients with early rheumatoid arthritis

would receive biological treatment, and less than half

would reach the low disease activity target allowing

them to stop after 6 months. Costs would skyrocket.

At a time of constraint in health-care budgets,

health-care providers should spend their money

wisely, and NICE should reset its economic model

for rheumatoid arthritis to include the outcomes of

modern combination therapy, treatment which it

itself recommends.9 For many patients, the intelligent

use of combination therapy including glucocorticoids

will eliminate the need for early biological therapy.

For patients who do need biological therapy and then

achieve stable low disease activity, the OPTIMA results

suggest it might be reasonable to consider switching

back to non-biological treatment.

We congratulate Smolen and colleagues for tackling

the problem of treating rheumatoid arthritis from a

new standpoint, for showing how a trial of stopping

treatment can be so informative, and for providing

a very useful opportunity for re-evaluating the best

possible role of routine combination therapy in the early

stages of this important disease.

*John R Kirwan, Maarten Boers

University of Bristol Academic Rheumatology Unit, Bristol Royal

Infi rmary, Bristol BS8 2UR, UK (JRK); and Department of

Epidemiology and Biostatistics, VU University Medical Center,

Amsterdam, Netherlands (MB)

[email protected]

We declare that we have no confl icts of interest.

1 Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in

rheumatoid arthritis on the basis of achievement of stable low disease

activity with adalimumab plus methotrexate or methotrexate alone: the

randomised controlled OPTIMA trial. Lancet 2013; published online Oct 26.

http://dx.doi.org/10.1016/S0140-6736(13)61751-1.

2 Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and

radiographic consequences of achieving stable low disease activity and

remission with adalimumab plus methotrexate or methotrexate alone in

early rheumatoid arthritis: 26-week results from the randomised,

controlled OPTIMA study. Ann Rheum Dis 2013; 72: 64–71.

3 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison

of treatment strategies in early rheumatoid arthritis: a randomized trial.

Ann Intern Med 2007; 146: 406–15.

4 Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of

combination therapy with single-drug therapy in early rheumatoid

arthritis: a randomised trial. Lancet 1999; 353: 1568–73.

5 Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in

a methotrexate-based, tight control strategy for early rheumatoid arthritis:

a randomized trial. Ann Intern Med 2012; 156: 329–39.

6 Kirwan JR, Bijlsma JWJ, Boers M, Shea B. Eff ects of glucocorticoids on

radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev

2007; 1: CD006356.

7 Kirwan JR. Combination therapy including glucocorticoids: the new gold

standard for early treatment in rheumatoid arthritis? Ann Intern Med 2012;

156: 390–91.

8 NICE. Adalimumab, etanercept and infl iximab for the treatment of

rheumatoid arthritis. Technology appraisals, TA 130—issues October, 2007.

http://www.nice.org.uk/TA130 (accessed Sept 25, 2013).

9 National Collaborating Centre for Chronic Conditions. Rheumatoid

arthritis: national clinical guideline for management and treatment in

adults. London: Royal College of Physicians, 2009.